TWILIGHT – Is It Possible To Drop Aspirin Post PCI?

Introduction

The use of dual antiplatelet therapy (DAPT) is the standard practice after percutaneous coronary intervention (PCI) with implantation of stents¹. The optimal duration of this regime has been the subject of various studies^2-7 (Table 1). Longer duration of DAPT had previously been perceived as the better option, reducing the risk of late or very late stent thrombosis after the implantation of first generation drug eluting stents (DES)⁸. Since newer generations of DES with better safety profile have been utilised in clinical practice, concerns about stent thrombosis have declined⁹, and have shifted towards the associated increased risk of bleeding with DAPT.

In the GLOBAL LEADERS trial², which was a randomised open label trial published in 2018, patients who received biolimus A9-eluting stent for stable coronary artery disease (CAD) or acute coronary syndrome (ACS) were assigned either to one month of aspirin and ticagrelor followed by 23 months of ticagrelor monotherapy, or to standard DAPT for 12 months post PCI [with aspirin plus either clopidogrel (for patients with stable CAD) or ticagrelor (for patients with ACS)], followed by aspirin monotherapy for another 12 month period. The trial failed to prove superiority of the former strategy (of ticagrelor monotherapy) to the latter at preventing all-cause mortality or new Q-wave myocardial infarction at 2 years following PCI (primary endpoint rate ratio 0·87 [95% CI 0·75–1·01]; p=0·073). No significant difference was noted on the subanalysis looking at the specific subgroups in the trial (stable CAD versus ACS patients). Furthermore, no statistically significant difference was found between the trial groups in the incidence of definite or probable stent thrombosis. The incidence of major bleeding (defined as Bleeding Academic Research Consortium [BARC] type 3 or 5) was not statistically different either between the two groups (2·04% vs 2·12%; rate ratio 0·97 [95% CI 0·78–1·20]; p=0·77), suggesting no additional safety benefit for the use of 1 month compared to 12 months of DAPT. However, this study was open label, and the risk profile of the population included was not particularly high compared to other studies like PEGASUS (5) and TWILIGHT³(GLOBAL LEADERS included all comers with stable CAD or ACS with no further specifications, while PEGASUS and TWILIGHT on the other hand specified additional criteria prior to enrolment that would imply higher bleeding and ischaemic risk).

P2Y12 inhibitor monotherapy was also trialled against DAPT in the SMART-CHOICE trial⁴, which was published in 2019. This was a randomised non inferiority trial, where the use of P2Y12 inhibitor monotherapy (clopidogrel, ticagrelor or prasugrel) after 3 months of DAPT was found non-inferior to the use of DAPT for 12 months in those who’d received DES for stable angina or ACS (The primary outcome was a composite of all-cause mortality, non-fatal MI and stroke at 12 months after the PCI procedure; incidence (2.9% vs 2.5%; difference, 0.4% [1-sided 95% CI, –∞% to 1.3%]; P = 0.007 for noninferiority)). Again, the trial design was open label, and the population enrolled was of relatively low risk, making the application of the results on a wider scale challenging.

Patients of higher clinical risk profile were studied in the PEGASUS-TIMI 54⁵ and the TWILIGHT³ trials. The PEGASUS-TIMI 54 trial looked into the extended use of DAPT with aspirin and ticagrelor, as compared with aspirin and placebo, beyond 12 months in those high risk patients who had spontaneous MI 1-3 years earlier. 83% of patients in each trial group had a history of PCI. While all patients were at least 50 years old, “high risk” was defined as having one of the following features: age of 65 years or older, a second prior spontaneous myocardial infarction, diabetes mellitus requiring medication, multivessel coronary artery disease, or chronic renal dysfunction, defined as an estimated creatinine clearance of less than 60 ml per minute. At 3 years, DAPT using ticagrelor as the P2Y12 inhibitor (whether at a dose of 90mg or 60 mg twice daily) significantly reduced the risk of cardiovascular death, MI or stroke (hazard ratio for 90 mg of ticagrelor vs. placebo, 0.85; 95% confidence interval [CI], 0.75 to 0.96; P=0.008; hazard ratio for 60 mg of ticagrelor vs. placebo, 0.84; 95% CI, 0.74 to 0.95; P=0.004) but increased the risk of Thrombolysis in Myocardial Infarction (TIMI) major bleeding (2.60% with 90 mg and 2.30% with 60 mg ticagrelor, 1.06% with placebo; p<0.001 for each dose vs. placebo)⁵.

The TWILIGHT trial is discussed in more detail in this editorial.

The TWILIGHT study:

The study design

The Ticagrelor With AspIrin or ALone In HiGHRisk Patients After Coronary InTervention (TWILIGHT) study³ is a randomised, multicentre, double blinded, placebo-controlled investigator-initiated trial, that was conducted in 11 countries (187 sites) between 2015 and 2019. A total of 9006 patients were initially enrolled, all of whom had received percutaneous coronary intervention (PCI) with at least one drug eluting stent (DES), and were discharged on DAPT with aspirin (81 to 100mg once daily) and ticagrelor (90mg twice daily). Additional inclusion criteria were the presence of at least one more clinical feature and at least one more angiographic feature known to be associated with high risk of ischaemic or bleeding events. Randomisation occurred at 3 months after discharge from hospital if the patient had not sustained an ischaemic event (stroke, (MI or coronary revascularisation), or a major bleeding event defined as BARC type 3b or higher. The main inclusion and exclusion criteria are summarised in Table 2.

1887 patients did not undergo randomisation for various reasons such as being lost to follow up, developing adverse events/ MI/ stroke/ BARC type 3b or higher bleeding event, receiving further revascularisation, nonadherence to DAPT, death, or withdrawal of consent. A total of 7119 patients were randomised in a 1:1 ratio to having either ticagrelor plus aspirin or ticagrelor plus placebo for 12 more months. Both arms of the trial were matched appropriately in age, race, gender, and body mass index. A similar prevalence of various medical conditions was also found in each trial group (e.g. diabetes mellitus, chronic kidney disease, anaemia, previous PCI or coronary artery bypass graft (CABG), peripheral vascular disease, etc.). Comparable numbers were seen in each trial group when stratifying by indications for PCI (see Table 3).

Primary and secondary end points

The study was powered to detect superiority for the primary end point which was the first occurrence of BARC type 2, 3, or 5 bleeding at any point in the 12 months following randomisation. The main secondary end point was the composite of death from any cause, nonfatal MI, or nonfatal stroke in the same period following randomisation, and this was assessed using a non-inferiority hypothesis. Other secondary bleeding end points included BARC type 3 or 5 bleeding; TIMI major or minor bleeding; Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) moderate, severe, or life-threatening bleeding; or major bleeding as defined by the International Society on Thrombosis or Haemostasis (ISTH). Additionally, secondary end points also included death from cardiovascular causes, MI (according to the third universal definition), ischemic stroke, and definite or probable stent thrombosis (based on the Academic Research Consortium). [Table 4 summarises the outcomes].

Results

The rate of occurrence of the primary end point (BARC type 2, 3 or 5 bleeding) in the ticagrelor and placebo group was almost half that of the ticagrelor and aspirin group (4.0% versus 7.1, with hazard ratio [HR] of 0.56, and 95% confidence interval [CI] of 0.45-0.68, p <0.001). Incidences of secondary bleeding end points as described above followed a similar trend to that of the primary bleeding end point, and were twice as common in the aspirin and ticagrelor group compared to the other group (see Table 3). There were no p-values given for the results of any of these secondary bleeding end points, but all HR were significant indicating superiority of the ticagrelor monotherapy after the first 3 months of DAPT.

The incidence of the key secondary end point, which was a composite of death from any cause, nonfatal MI, or nonfatal stroke, was not different between both trial arms with incidence of 3.9% (experimental arm) vs 3.9% (control arm), HR of 0.99, CI of 0.78-1.25, and P value of <0.001. Similarly, the incidence of other ischaemic end points was comparable in both arms (see Table 4). The TWILIGHT trial concluded that patients with high bleeding or ischaemic risk, who underwent PCI for various indications and then completed 3 months of DAPT with aspirin and ticagrelor followed by 12 months on ticagrelor monotherapy had lower rates of clinically relevant bleeding compared to those who continued on DAPT for a further 12 months. Ticagrelor monotherapy was also found non inferior to DAPT in reducing risk of death from any cause, and risk of nonfatal MI or stroke.

The trial was well designed and powered to detect superiority of monotherapy for bleeding outcomes. The results were consistent even when different scoring systems were used to define significant bleeding. Even though the trial was not powered to detect differences in the incidence of ischaemic stroke or that of probable or definite stent thrombosis, it was able to prove non-inferiority of ticagrelor monotherapy to DAPT with respect to the composite end point of all death, MI or stroke. Being a double blinded trial not only helped minimise the chance of bias, but also separated this trial from others - such as the GLOBAL LEADERS and the SMART-CHOICE trials^2,4, that also studied P2Y12 inhibitor monotherapy versus DAPT strategy after PCI.

Additionally, the population recruited in theTWILIGHT trial also differed as they were deemed to be at high risk of ischaemic or bleeding events compared to those in the other trials. Referring to Table 5, it is clear that the observed bleeding event rates were particularly high (at 7.1%) in the TWILIGHT trial compared to the others. However, in regards to major adverse cardiovascular events (MACE), the TWILIGHT appears to be in fact underpowered, as the expected event rates were 8% while the observed ones were only 3.9%. While STEMI patients were excluded from the TWILIGHT trial, near 1000 patients with stable angina were included in each trial arm (29.5% in the ticagrelor plus placebo group, and 28% in the ticagrelor plus aspirin group). This seems odd as the contemporary guidelines recommend the use of clopidogrel rather than ticagrelor in addition to aspirin after PCI in this category of patients. Furthermore, the recommended duration of DAPT in such patients is usually 6 months (though continuation of DAPT with clopidogrel for > 6 months has class IIb indication in certain patients)¹. It is also important to note that about 6% of patients in each trial group received PCI when they were asymptomatic. The inclusion of more stable patients with presumably lower expected ischaemic event rates might favour an overall trend of lower ischaemic event rates in the study population at the expense of increased bleeding event rates.

Finally, despite the clear bleeding benefit seen when using ticagrelor monotherapy in this study population, it is important to note that patients who had actually developed more significant bleeding were not randomised in the first place and were excluded at 3 months post PCI. Moreover, while 5- 10% of the PCI population have atrial fibrillation¹⁰, the results of the TWILIGHT trial cannot be applied to this subgroup of patients who require anticoagulation.

Conclusion

The TWILIGHT study provides evidence of lower incidence of bleeding in patients at high risk of ischaemic or bleeding events (as defined in the study design) who had undergone PCI and completed 3 months of DAPT and then were treated with ticagrelor monotherapy for 12 months. Such a strategy was also found non-inferior to DAPT for the composite of all cause death, MI or stroke. But in fact, it may well be that adding aspirin to P2Y12 inhibitors provides extra risk with no added benefits, and that the well-established benefits of DAPT are actually driven by the effect of potent P2Y12 inhibitors rather than being the outcome of the combination therapy. This might actually advise change in guidelines and result in the default use of monotherapy with potent antiplatelet agents post PCI. Further research is also needed explore whether the results of the TWILIGHT trial can be replicated with the use of other thienopyridines, and to test the possible use of P2Y12 inhibitor monotherapy lifelong as a replacement to aspirin.

Disclosures

None.

References

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